Incidence and Mortality

Estimated new cases and deaths from pancreatic cancer in the United States in 2019:[1]

New cases: 56,770.

Deaths: 45,750.

The incidence of carcinoma of the pancreas has markedly increased over the past several decades and ranks as the fourth leading cause of cancer death in the United States. Despite the high mortality rate associated with pancreatic
cancer, its etiology is poorly understood.[2]

Risk Factors

Risk factors for development of pancreatic cancer include the following:[3,4]

A family history of pancreatic cancer.

Cigarette smoking.

Obesity.

Chronic pancreatitis.

Certain genetic disorders (such as those associated with the BRCA1, BRCA2, PALB2, and ATM genes).

Anatomy

Cancers of the pancreas are commonly identified by the site of involvement within the pancreas. Surgical approaches differ for masses in the head, body, tail, or uncinate process of the pancreas.

Clinical Features

Pancreatic cancer symptoms depend on the site of the tumor within the pancreas and the degree of tumor involvement.

In the early stages of pancreatic cancer there are not many noticeable symptoms. As the cancer grows, symptoms may include the following:

Jaundice.

Light-colored stools or dark urine.

Pain in the upper or middle abdomen and back.

Weight loss for no known reason.

Loss of appetite.

Fatigue.

Diagnostic and Staging Evaluation

Pancreatic cancer is difficult to detect and diagnose for the following reasons:

There are no noticeable signs or symptoms in the early stages of pancreatic cancer.

The signs of pancreatic cancer, when present, are like the signs of many other illnesses, such as pancreatitis or an ulcer.

The pancreas is obscured by other organs in the abdomen and is difficult to visualize clearly on imaging tests.

To appropriately treat pancreatic cancer, it is crucial to evaluate whether the cancer can be resected.

Imaging

The use of imaging technology may aid in the diagnosis of pancreatic cancer and in the identification of patients with
disease that is not amenable to resection. Imaging tests that may be used include the following:[5]

Helical computed tomographic scan.

Magnetic resonance imaging scan.

Endoscopic ultrasonography.

Minimally invasive techniques, such as laparoscopy and laparoscopic ultrasonography may be used to decrease the use of laparotomy.[6,7]

Peritoneal cytology

In a case series of 228 patients, positive peritoneal cytology had a positive predictive value of 94%, specificity of 98%, and sensitivity of 25% for determining unresectability.[8]

Tumor markers

No tumor-specific markers exist for pancreatic cancer; markers such as serum cancer antigen (CA) 19-9 have low specificity. Most patients with pancreatic cancer will have an elevated CA 19-9 at diagnosis. Following or during definitive therapy, the increase of CA 19-9 levels may identify patients with progressive tumor growth.[9][Level of evidence: 3iDiii] The presence of a normal CA 19-9, however, does not preclude recurrence.

Prognosis and Survival

The primary factors that influence prognosis are:

Whether the tumor is localized and can be completely resected.

Whether the tumor has spread to lymph nodes or elsewhere.

Exocrine pancreatic cancer is rarely curable and has an overall survival (OS) rate of less than 6%.[10]

The highest cure rate occurs when the tumor is truly localized to the pancreas; however, this stage of disease accounts for less than 20% of cases. For patients with localized disease and small cancers (<2 cm) with no lymph node metastases and no extension beyond the capsule of the pancreas, complete surgical resection is associated with an actuarial 5-year survival rate of 18% to 24%.[11][Level of evidence: 3iA]

Surgical resection is the mainstay of curative treatment and provides a survival benefit in patients with small, localized pancreatic tumors. Patients with unresectable, metastatic, or recurrent disease are unlikely to benefit from surgical resection.

Pancreatic tumors are resistant to treatment with chemotherapy and radiation.

Patients with any stage of pancreatic cancer can appropriately be considered
candidates for clinical trials because of the poor response to chemotherapy,
radiation therapy, and surgery as conventionally used.

Palliative Therapy

Palliation of symptoms may be achieved with conventional treatment.

Palliative measures that may improve quality of life while not affecting OS include the following:[12,13]

Surgical or radiologic biliary decompression.

Relief of gastric outlet obstruction.

Pain control.

Psychological care to address the potentially disabling psychological events associated with the diagnosis and treatment of pancreatic cancer.[14]

Stage Information for Pancreatic Cancer

The staging system for pancreatic exocrine cancer continues to evolve. The importance of staging beyond establishing whether a tumor is resectable is uncertain because state-of-the-art treatment has demonstrated little impact on survival. However, knowledge of the extent of the disease is necessary to communicate a uniform definition of disease.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification.[1]

References

Treatment Option Overview for Pancreatic Cancer

Surgical resection remains the primary modality when feasible; on occasion, resection can lead to long-term survival and provides effective palliation.[1-3][Level of evidence: 3iA]

The role of postoperative therapy (chemotherapy with or without chemoradiation therapy) in the management of pancreatic cancer remains controversial because much of the randomized clinical trial data available are statistically underpowered and provide conflicting results.[4-8]

Complications of pancreatic cancer include the following:

Malabsorption: Frequently, malabsorption caused by exocrine insufficiency contributes to malnutrition. Attention to pancreatic enzyme replacement can help alleviate this problem. (Refer to the PDQ summary on Nutrition in Cancer Care for more information.)

Pain: Celiac axis and intrapleural nerve blocks can provide highly effective and long-lasting control of pain for some patients. (Refer to the PDQ summary on Cancer Pain for more information.)

The survival rate of patients with any stage of pancreatic exocrine cancer is poor. Clinical trials are appropriate alternatives for treatment of patients with any stage of disease and should be considered before palliative approaches are selected.

Information about ongoing clinical trials for pancreatic cancer is available from the NCI website.

Surgery

Complete resection can yield 5-year survival rates of 18% to 24%, but ultimate control remains poor because of the high incidence of both local and distant tumor recurrence. Thus, concurrent systemic therapy is recommended for treatment.[9-11][Level of evidence: 3iA]

Approximately 20% of patients present with pancreatic cancer amenable to local surgical resection, with operative mortality rates of approximately 1% to 16%.[12-16] Using information from the Medicare claims database, a national cohort study of more than 7,000 patients undergoing pancreaticoduodenectomy between 1992 and 1995 revealed higher in-hospital mortality rates at low-volume hospitals (<1 pancreaticoduodenectomy per year) versus high-volume hospitals (>5 per year) (16% vs. 4%, respectively; P < .01).[12]

For patients with good performance status, adjuvant FOLFIRINOX (oxaliplatin leucovorin, irinotecan, and 5-FU) chemotherapy or the combination of gemcitabine and capecitabine should be considered. However, for older patients or patients with marginal performance status, adjuvant gemcitabine or 5-FU monotherapy can be considered. In Asia, S-1 (tegafur-gimeracil-oteracil potassium) is an appropriate alternative to gemcitabine-based therapies.

Toxicity was higher with combination therapy; 75.9% of patients treated with FOLFIRINOX had grade 3/4 toxicities (compared with 52.9% of those who received gemcitabine), with similar rates of neutropenia (although 62.2% of patients on FOLFIRINOX received granulocyte colony-stimulating factor). Thirty-three percent of patients who received FOLFIRINOX stopped treatment prematurely, compared with 21% of patients who received gemcitabine alone.

Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 [NCT00058201]) trial randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone (1,000 mg/m2 administered weekly for 3 weeks of every 4 weeks) or oral capecitabine (1,660 mg/m2 administered for 21 days followed by 7 days of rest [one cycle]).[19][Level of evidence: 1iiA]

With a median follow-up of 43.2 months, the median OS for patients in the gemcitabine/capecitabine group was 28.0 months (95% CI, 23.5–31.5) compared with 25.5 months for the gemcitabine-alone group (95% CI, 22.7–27.9; HR, 0.82; P = .032). Treatment with gemcitabine/capecitabine yielded an improvement in estimated 5-year OS from 16.3% with gemcitabine alone to 28.8% with gemcitabine/capecitabine.

There was no significant effect on the quality of life in the treatment groups.

On the basis of these findings, the adjuvant combination of gemcitabine and capecitabine should be the new standard of care after a resection for pancreatic cancer.

S-1: The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study was a phase III, multicenter, noninferiority trial in Japan that randomly assigned 385 patients to receive either gemcitabine (1,000 mg/m2 administered weekly for 3 weeks of every 4 weeks) for six cycles or tegafur-gimeracil-oteracil potassium (S-1) (administered orally bid for 4 weeks then followed by a 2-week break).[20][Level of evidence: 1iiA]

The prespecified criteria for early discontinuation was met at interim analysis for efficacy with all of the protocol treatments completed. On early interim analysis, the HRmortality was 0.57 (95% CI, 0.44–0.72; P for noninferiority < .001, P for superiority < .001). These results were associated with a 5-year OS of 24.4% in the gemcitabine group and 44.1% in the S-1 group.

Grade 3/4 leukopenia, neutropenia, and liver transaminitis were observed more frequently in the gemcitabine group, and stomatitis and diarrhea were experienced more frequently in the S-1 group.

Among Japanese patients, adjuvant chemotherapy with S-1 can be a new standard of care for resected pancreatic patients. Additional studies are needed to validate these results in non-Asian patients.

The pharmacokinetics and pharmacodynamics of S-1 may be different between Eastern and Western patient populations because grade 3/4 gastrointestinal toxicities, especially diarrhea, have been reported more commonly in the Western patient population. S-1 is not currently approved by the U.S. Food and Drug Administration for use in the United States.

Gemcitabine: Charité Onkologie (CONKO)-001 was a multicenter phase III trial of 368 patients with resected pancreatic cancer who were randomly assigned to receive six cycles of adjuvant gemcitabine versus observation.[17][Level of evidence: 1iiDii] In contrast to the previous trials, the primary endpoint was DFS.

With a median follow-up of 136 months, long-term follow-up of the CONKO-001 study demonstrated a significant improvement in OS that favors gemcitabine (median survival, 22.8 months vs. 20.2 months; HR, 0.76; 95% CI, 0.61–0.95, P = .01). Gemcitabine compared with observation alone yielded improved survival rates at 5 years of 20.7% for the gemcitabine arm versus 10.4% for the observation-alone arm, and the survival rates at 10 years were 12.2% for the gemcitabine arm versus 7.7% for the observation-alone arm.[21][Level of evidence: 1iiA]

Gemcitabine or 5-FU: The ESPAC-3 (NCT00058201) trial randomly assigned 1,088 patients who had undergone complete macroscopic resection to either 6 months of 5-FU (425 mg/m2) and leucovorin (20 mg/m2) on days 1 to 5 every 28 days or 6 months of gemcitabine (1,000 mg/m2) on days 1, 8, and 15 every 28 days.[3][Level of evidence: 1iiA]

Postoperative chemoradiation therapy

The role of postoperative therapy (chemotherapy with or without chemoradiation therapy) in the management of this disease remains controversial because much of the randomized clinical trial data available are statistically underpowered and provide conflicting results.[4-8]

The investigators reported a significant but modest improvement in median-term and long-term survival over resection alone with postoperative bolus 5-FU and regional split-course radiation given at a dose of 40 Gy.

European Organization for the Research and Treatment of Cancer (EORTC): An attempt by the EORTC to reproduce the results of the GITSG trial failed to confirm a significant benefit for adjuvant chemoradiation therapy over resection alone;[6][Level of evidence: 1iiA] however, this trial treated patients with pancreatic and periampullary cancers (with a potentially better prognosis).

An updated analysis of a subsequent ESPAC-1 trial examined only patients who underwent strict randomization after pancreatic resection. The patients were assigned to one of four groups (observation, bolus 5-FU chemotherapy, bolus 5-FU chemoradiation therapy, or chemoradiation therapy followed by additional chemotherapy).[7,8,22][Level of evidence: 1iiA]

With a 2 × 2 factorial design reported at a median follow-up of 47 months, a median survival benefit was observed for only the patients who received postoperative 5-FU chemotherapy. However, these results were difficult to interpret because of a high rate of protocol nonadherence and the lack of a separate analysis for each of the four groups in the 2 × 2 design.

U.S. Gastrointestinal Intergroup: The U.S. Gastrointestinal Intergroup has reported the results of a randomized phase III trial (Radiation Therapy Oncology Group [RTOG]-9704) that included 451 patients with resected pancreatic cancers who were assigned to receive either postoperative infusional 5-FU plus infusional 5-FU and concurrent radiation or adjuvant gemcitabine plus infusional 5-FU and concurrent radiation.[23][Level of evidence: 1iiA] The primary endpoints were OS for all patients and OS for patients with pancreatic head tumors.

Univariate analysis showed no difference in OS; however, on multivariate analysis, patients on the gemcitabine arm with pancreatic head tumors experienced a trend toward improved OS (P = .08). Distant relapse remained the predominant site of first failure (78%).

A secondary analysis of RTOG-9704 explored the correlation of adherence to protocol-specified radiation with patient outcomes.[25][Level of
evidence: 1iiA]

Radiation therapy adherence was scored as per protocol (n = 216) and less than per protocol (n = 200). The major deviation seen was deviation in field size and field placement.

For all pancreatic sites, median survival for patients per protocol was significantly longer than patients treated less than per protocol (1.74 years vs. 1.46 years; P = .008).

On multivariate analysis, treatment per protocol correlated more strongly with median survival than assigned treatment arm (P = .014). However, this is an exploratory analysis that cannot control for potential unknown confounders.

The EORTC/U.S. Gastrointestinal Intergroup RTOG-0848 phase III adjuvant trial evaluating the impact of chemoradiation therapy after completion of a full course of gemcitabine with or without erlotinib is currently enrolling patients.

Additional trials are still warranted to determine more effective systemic therapy for this disease.

Treatment Options Under Clinical Evaluation for Stages I and II Pancreatic Cancer

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Stage III Pancreatic Cancer Treatment

Treatment Options for Stage III Pancreatic Cancer

While stage III and stage IV pancreatic cancer are both incurable, the natural history of stage III (locally advanced) disease may be different than it is for stage IV disease. An autopsy series demonstrated that 30% of patients presenting with stage III disease died without evidence of distant metastases.[1][Level of evidence: 1iiA] Therefore, investigators have struggled with the question of whether chemoradiation for patients presenting with stage III disease is warranted.

Chemotherapy

Chemotherapy is the primary treatment modality for patients with locally advanced pancreatic cancers and uses the same regimens as those used to treat patients with metastatic disease.

Evidence (chemotherapy):

Gemcitabine versus 5-fluorouracil (5-FU): Gemcitabine has demonstrated activity in patients with pancreatic
cancer and is a useful palliative agent.[4-6] A phase III trial of gemcitabine
versus 5-FU as first-line therapy in patients with advanced or metastatic
adenocarcinoma of the pancreas reported a significant improvement in survival
among patients treated with gemcitabine (1-year survival was 18% with
gemcitabine compared with 2% with 5-FU; P = .003).[5][Level of
evidence: 1iiA]

Gemcitabine alone versus gemcitabine and erlotinib: The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 [NCT00026338]) that compared gemcitabine alone with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[7][Level of evidence: 1iiA]

The corresponding median and 1-year survival rates for patients who received erlotinib versus placebo were 6.2 months and 5.9 months, and 23% versus 17%, respectively.

Platinum analog or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analog (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.[8,9]

Not one of these phase III trials has demonstrated a statistically significant advantage favoring the use of combination chemotherapy in the first-line treatment of metastatic pancreatic cancer.

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma (Karnofsky Performance Status of ≥70) who had not previously received chemotherapy for metastatic disease.[10][Level of evidence: 1iiA] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

The median overall survival (OS) was 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HRdeath, 0.72; 95% CI, 0.62–0.83; P < .001).

Median progression-free survival was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HRdisease progression, 0.69; 95% CI, 0.58–0.82; P < .001).

Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities were neutropenia (38% in the nab-paclitaxel/gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group), and neuropathy (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group). Febrile neutropenia occurred in 3% of the nab-paclitaxel/gemcitabine group versus 1% in the gemcitabine group. In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% were able to resume treatment at a reduced dose within a median of 23 days after onset of a grade 3 event.

On the basis of this trial, nab-paclitaxel/gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.

Quality-of-life data have not yet been published regarding this regimen, and this study does not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.

FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an ECOG performance status score of 0 or 1.[11][Level of evidence: 1iiA] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and 5-FU [400 mg/m2] given as a bolus followed by 2,400 mg/m2 given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

The median OS was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (HRdeath, 0.57; 95% CI, 0.45–0.73; P < .001).

Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HR for disease progression, 0.47; 95% CI, 0.37–0.59; P < .001).

FOLFIRINOX was more toxic than gemcitabine; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of quality of life, versus 66% in the gemcitabine group (HR, 0.47; 95% CI, 0.30–0.70; P < .001).

On the basis of this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.

5-FU, leucovorin, and oxaliplatin (OFF regimen) versus best supportive care (BSC): Second-line chemotherapy after progression on a gemcitabine-based regimen may be beneficial. The Charité Onkologie (CONKO)-003 investigators randomly assigned patients in the second line of chemotherapy to either the OFF regimen or BSC.[12]; [13][Level of evidence: 3iA] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24-hour continuous infusion] on days 1, 8, 15, and 22) and oxaliplatin (85 mg/m2 on days 8 and 22). After a rest of 3 weeks, the next cycle was started on day 43. The trial was terminated early because of poor accrual, and only 46 patients were randomly assigned to either the OFF regimen or BSC.

Median OS was 9.09 months for the sequence of gemcitabine/OFF and 7.90 months for gemcitabine/BSC.

The early closure of the study and the very small number of patients made the P values misleading. Therefore, second-line chemotherapy with the OFF regimen may be falsely associated with improved survival.

Three trials attempted to look at combined modality therapy versus radiation therapy alone.[14-16] The trials had substantial deficiencies in design or analysis. Initially, the standard of practice was to give chemoradiation therapy based on data from the first two studies; however, with the publication of the third study, standard practice has changed to chemotherapy followed by chemoradiation in the absence of metastases.

LAP07 (NCT00634725): The LAP07 study was an international, randomized phase III study based on the results of the Groupe Coopérateur Multidiciplinaire en Oncologie (GERCOR) study. In total, 449 patients were enrolled between 2008 and 2011, with random assignment via a two-step randomization process. In the first step, patients were randomly assigned to induction gemcitabine (n = 223) or gemcitabine plus erlotinib (n = 219) for four cycles. For the second step, patients with controlled tumors were randomly assigned (n = 269) a second time to receive either chemotherapy (n = 136) or chemoradiation therapy (n = 133). A total dose of 54 Gy in 30 daily fractions was prescribed with concurrent capecitabine at a dose of 800 mg/m2 twice daily on days of radiation therapy.[18][Level of evidence: 1iiA]

The primary endpoint was OS. After interim analysis, the study was stopped early because of futility.

With a median follow-up of 36.7 months, the median OS from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5–18.5 months) and chemoradiation therapy at 15.2 months (95% CI, 13.9–17.3 months, P = .83).

Median OS after the first randomization was 13.6 months (95% CI, 12.3–15.3 months) for the patients who received gemcitabine and was 11.9 months (95% CI, 10.4–13.5 months, P = .09) for the patients who received gemcitabine plus erlotinib.

The LAP07 study represents the most robust, prospective, randomized phase III data regarding the role of chemoradiation therapy in the setting of gemcitabine-based induction chemotherapy that demonstrates no OS benefit. However, this study was initiated before the advent of FOLFIRINOX chemotherapy, which has been widely adopted into the locally advanced setting. The role of chemoradiation in the setting of more active chemotherapy regimens, including gemcitabine/paclitaxel and FOLFIRINOX, has yet to be evaluated.

The study was stopped early when the chemoradiation therapy groups were found to have better efficacy. The 1-year survival was 11% for patients who received EBRT alone compared with 38% for patients who received chemoradiation therapy with 40 Gy and 36% for patients who received chemoradiation therapy with 60 Gy.

After an additional 88 patients were enrolled in the combined modality arms, there was a trend toward improved survival with 60 Gy EBRT plus 5-FU, but the difference in time-to-progression and OS was not statistically significant when compared with the 40 Gy arm.[19]

Fédération Francophone de Cancérologie Digestive-Société Française de Radiothérapie Oncologie (FFCD-SFRO) trial: As it became clear that radiation therapy alone was an inadequate treatment, investigators evaluated combined modality approaches versus chemotherapy alone. Investigators from the FFCD-SFRO randomly assigned 119 patients to induction chemoradiation therapy (60 Gy in 2 Gy fractions with 300 mg/m2/d of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2/d of cisplatin on days 1–5 during weeks 1 and 5) or induction gemcitabine (1,000 mg/m2 weekly for 7 weeks). Maintenance gemcitabine was administered to both groups until stopped by disease progression or treatment discontinuation as a result of toxicity.[20][Level of evidence: 1iiA]

Nonetheless, the survival benefit persisted in a per-protocol analysis of patients receiving at least 75% of planned therapy. Notably, the dose intensity of maintenance gemcitabine was significantly less in the chemoradiation therapy group because of a greater incidence of grades 3 to 4 hematological toxicities (71% vs. 27%; P = .0001).

As a result of this study, induction chemoradiation therapy has fallen out of favor.

ECOG: The results of the FFCD-SFRO study stand in contrast to the results of a study from ECOG in which investigators randomly assigned 74 patients to either gemcitabine alone or gemcitabine with radiation followed by gemcitabine.[17] Of note, the study was closed early as the result of poor accrual.

Grades 4 and 5 toxicity were greater in the chemoradiation therapy arm than in the chemotherapy arm (41% vs. 9%).

GERCOR: Given the increased toxicity of chemoradiation therapy and the early development of metastatic disease in a large percentage of patients with stage III pancreatic cancer, investigators are pursuing a strategy of selecting patients with localized disease for chemoradiation therapy. With this strategy, the selected patients have an absence of progressive disease locally or systemically after several months of chemotherapy.[21][Level of evidence: 3iiiA]

Palliative surgery

A significant proportion (approximately one-third) of patients with pancreatic cancer will present with stage III or locally advanced disease. Patients with stage III pancreatic cancer have tumors that are technically unresectable because of local vessel impingement or invasion by tumor. However, with the combination of chemotherapy and chemoradiation, some patients may become surgical candidates. Patients may benefit from palliation of biliary obstruction by endoscopic, surgical, or radiological means.[22]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Chemotherapy

Because of the low objective response rate and limited efficacy of palliative chemotherapy regimens, enrollment into clinical trials should be considered for all newly diagnosed patients. Multiagent chemotherapy combinations have recently been shown to prolong outcomes compared with single-agent gemcitabine.[5-7]

Evidence (single-agent chemotherapy):

Gemcitabine versus 5-fluorouracil (5-FU): A phase III trial of gemcitabine versus 5-FU as first-line therapy in patients with advanced or metastatic adenocarcinoma of the pancreas reported a significant improvement in survival among patients treated with gemcitabine (1-year survival was 18% with gemcitabine vs. 2% with 5-FU; P = .003).[5][Level of evidence: 1iiA]

Evidence (multiagent chemotherapy):

FOLFIRINOX (leucovorin calcium, 5-FU, irinotecan hydrochloride, and oxaliplatin) versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1.[8][Level of evidence: 1iiA] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and 5-FU [400 mg/m2] given as a bolus followed by 2,400 mg/m2 given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HR for disease progression, 0.47; 95% CI, 0.37–0.59; P < .001).

FOLFIRINOX was more toxic than gemcitabine; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of quality of life versus 66% in the gemcitabine group (HR, 0.47; 95% CI, 0.30–0.70; P < .001).

On the basis of this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.

Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma (Karnofsky Performance Status of ≥70) who had not previously received chemotherapy for metastatic disease.[9][Level of evidence: 1iiA] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).

The median OS was 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HRdeath, 0.72; 95% CI, 0.62–0.83; P < .001).

Median progression-free survival was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HRdisease progression, 0.69; 95% CI, 0.58–0.82, P < .001).

Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities were neutropenia (38% in the nab-paclitaxel/gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group), and neuropathy (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group). Febrile neutropenia occurred in 3% of the nab-paclitaxel group versus 1% in the gemcitabine group. In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% were able to resume treatment at a reduced dose within a median of 23 days after onset of a grade 3 event.

On the basis of this trial, nab-paclitaxel plus gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.

Quality-of-life data have not yet been published regarding this regimen, and this study does not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.

Gemcitabine alone versus gemcitabine and erlotinib: The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 [NCT00026338]) that compared gemcitabine alone with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[10][Level of evidence: 1iiA]

Nanoliposomal irinotecan with or without 5-FU and folinic acid: The NAPOLI-1 trial (NCT01494506) evaluated the role of nanoliposomal irinotecan in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies.[11] Nanoliposomal irinotecan is an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. In this study, a total of 417 patients were randomly assigned to either nonliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks; n = 151), 5-FU and folinic acid (n = 149), or nanoliposomal irinotecan (80 mg/m2 every 2 weeks plus 5-FU) and folinic acid (n = 117).[11][Level of evidence: 1iiD]

Despite differences in survival and toxicity between regimens, quality of life was not significantly different between treatment groups.

The benefit of using nanoliposomal irinotecan rather than unencapsulated irinotecan has not been established because the regimen for the control arm of this study was 5-FU/folinic acid. Additionally, the value of using nanoliposomal irinotecan after FOLFIRINOX in the first-line setting is not clear.

5-FU, leucovorin, and oxaliplatin (OFF regimen) versus best supportive care (BSC): Second-line chemotherapy after progression on a gemcitabine-based regimen may be beneficial. The Charité Onkologie (CONKO)-003 investigators randomly assigned patients in the second line of chemotherapy to either an OFF regimen or BSC.[6]; [7][Level of evidence: 3iA] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24 hours continuous infusion] on days 1, 8, 15, and 22) and oxaliplatin (85 mg/m2 on days 8 and 22). After a rest of 3 weeks, the next cycle was started on day 43. The trial was terminated early because of poor accrual, and only 46 patients were randomly assigned to either the OFF regimen or BSC.

Median OS was 9.09 months for the sequence of gemcitabine/OFF and 7.90 months for gemcitabine/BSC.

The early closure of the study and the very small number of patients made the P values misleading. Therefore, second-line chemotherapy with the OFF regimen may be erroneously associated with improved survival.

Overall response rate and quality of life was not significantly different in the two arms.

The overall incidence of grade 3/4 adverse events was 63% in the mFOLFOX-6 arm versus 11% in the 5-FU/LV arm. However, more patients in the mFOLFOX-6 arm withdrew from the study because of adverse events than did patients in the 5-FU/LV arm (20% vs. 2%).

On the basis of this study, no benefit was seen with the addition of oxaliplatin, administered in the mFOLFOX-6 regimen, versus infusional 5-FU/LV among patients with advanced pancreatic cancer after first-line gemcitabine-based chemotherapy. These results may suggest that oxaliplatin-based regimens for metastatic pancreatic cancer may yield the greatest benefit in the first-line setting.

Clinical trials evaluating new anticancer agents alone or in combination with chemotherapy.[13-17]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Added text to the surgery subsection to state that concurrent systemic therapy is recommended for treatment.

Revised text to state that for patients with good performance status, adjuvant FOLFIRINOX (oxaliplatin leucovorin, irinotecan, and 5-FU) chemotherapy or the combination of gemcitabine and capecitabine should be considered. Added that in Asia, S-1 (tegafur-gimeracil-oteracil potassium) is an appropriate alternative to gemcitabine-based therapies.

Revised text to state that chemotherapy is the primary treatment modality for patients with locally advanced pancreatic cancers and utilizes the same regimens as those used to treat patients with metastatic disease.

Added text to state that with the combination of chemotherapy and chemoradiation, some patients may become surgical candidates.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pancreatic cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Pancreatic Cancer Treatment is:

Valerie Lee, MD (Johns Hopkins University)

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Levels of Evidence

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Updated: March
28, 2019

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